tbuckley/cabot-search huggingface dataset:
Abstract 15318: Global Deletion of P90 Ribosomal S6 Kinase Provides Cardiovascular Protection Against Age-Related Hypertension
Authors: Ramon J Ayon, Yves T Wang, Jaspreet Kalra, Zaneta Markowska, Swapnil K Sonkusare, Thu H Le, Avril V Somlyo
Journal: Circulation (2022)

Background: Hypertension (HT) is highly prevalent and associated with significant mortality and morbidity among older individuals. Aging is associated with structural and functional remodeling of the vasculature, similar to blood vessel alterations observed in HT. We previously demonstrated that young adult global Rsk2 KO mice had more dilated mesenteric arteries (MAs), with reduced vessel tone, stiffness and RLC 20 phosphorylation, and significantly lower basal blood pressure compared to WT. However, it is unknown whether RSK2 plays a role in age-related HT. Hypothesis: Loss of RSK2 signaling in aged mice inhibits age-related- and L-NAME-induced HT, arterial stiffness, and vascular remodeling. Methods: Systolic blood pressure (SBP) measurements of &gt;24-month-old global Rsk2 KO and WT males were performed daily for 2 weeks after 2 weeks of daily training using tail cuff manometry. Baseline echocardiographic (echo) parameters were measured. N(G)-Nitro-L-arginine-methyl ester (L-NAME) was administered (20 mg/kg/day) via drinking water to induce HT. Pressure myography studies assessed vascular reactivity and arterial stiffness in MAs isolated from Rsk2 KO and WT mice. Aorta and MAs were sectioned and stained to examine structural changes. Results: WT mice had a significantly higher mortality rate (63.6%) compared to Rsk2 KO (12.5%). Baseline SBP was also significantly higher in WT compared to KOs (123±10 vs. 99±12 mmHg, p &lt; 0.001, n = 9/7). L-NAME elevated SBP in WT but not in KO mice (137±2 vs. 97±8 mmHg, p &lt; 0.00001, n = 4/7). Although there were no differences in echo parameters, we observed a negative correlation between ejection fraction (EF) and SBP in WT (-0.94 %/mmHg, p = 0.046, R 2 = 0.59, n = 6), but not in Rsk2 KO mice (p = 0.15, n = 7). Functional and histological studies in aged KO mice are ongoing to examine age-related changes in vascular reactivity and remodeling. Conclusion: Loss of RSK2 reduces BP levels in aged mice akin to young adult mice. Additionally, the hypertensive effects of L-NAME are absent in aged Rsk2 KO mice. Aged Rsk2 KO mice appear to be protected from cardiovascular effects associated with age-related HT. Therapeutic targeting of RSK2 could prove beneficial for reducing risk of cardiovascular diseases associated with HT in the elderly.
Abstract 15123: Post-Infarction Inflammation Influences Diastolic Function After STEMI
Authors: Simon Leboube, Smaranda Filip, AHMAD HAYEK, Alexandre Paccalet, Camille Brun, Claire Crola Da Silva, Cyril PRIEUR, Eric BONNEFOY-CUDRAZ, Helene Thibault, Cyrille Bergerot, Nathan Mewton, Gilles Rioufol, Laura MECHTOUFF, Thomas Bochaton
Journal: Circulation (2022)

Introduction: Diastolic dysfunction after STEMI is under documented despite its impact on cardiovascular events. We focused on inflammatory biomarkers within hours after STEMI and their association with diastolic dysfunction at one month post STEMI. Hypothesis: Our aim was to identify an inflammatory profile promoting diastolic dysfunction in STEMI patients. Methods: We prospectively included STEMI patients admitted in our hospital from 2016 to 2019. We collected sera at 5 time points (admission (H0), 4 hours (H4), H24, H48 an 1 month). Inflammatory biomarkers serum levels were assessed using ELISA assays (cytokines, chemokines and endothelial activation biomarkers). Transthoracic echocardiogram and cardiac MRI to assess diastolic function and infarct size were carried out at one month post STEMI. We used last guidelines from the EACVI to grade diastolic function. Patients were followed for 12 months. Results: Complete echocardiographic data were available for 236 patients. There were 163 patients with normal diastolic function and 73 patients with diastolic dysfunction. As expected, patients with diastolic dysfunction had higher BNP level (197.0 ng/L versus 68 ng/L, p&lt;0.001) and were more likely to have a MACE during the first 12 months after STEMI compared to patients normal diastolic function (HR = 3.0 CI [1.1-7.9], p = 0.01). Patients with diastolic dysfunction at one month had higher inflammatory biomarkers within the first 48h post STEMI compared with patient with normal diastolic function: CRP AUC (660.2 mg.h.L -1 vs 361.4 mg.h.L -1 p=0.02), IL-6 AUC (206.0 pg.h.mL -1 vs 173.1 pg.h.mL -1 p=0.03) sTNFR1 AUC (27.6 ng.h.mL -1 versus 24.1 ng.h.mL -1 , p=0.03), sTNFR2 AUC (44.7 ng.h.mL -1 vs 43.5 ng.h.mL -1 , p=0.03) sST2 AUC (30.4 pg.h.mL -1 vs 27.3 pg.h.mL -1 , p=0.046), GDF15 AUC (10.8 ng.h.mL -1 vs 8.1 ng.h.mL -1 , p=0.050) and IL-10 AUC (174.6 pg.h.mL -1 vs 122.8 pg.h.mL -1 , p=0.02). There was no significant difference in infarct size (13 versus 17% of left ventricular mass, p = 0.06) or LVEF (58 versus 54%, p = 0.0523) between the two groups. Conclusions: Diastolic function seems influenced by the early post STEMI inflammatory environment. These results should be considered in future mechanistical study and in patients’ care.
Abstract 15063: Liver Gene Regulatory Mechanisms of Variants at Lipid and Cardio Metabolic Trait Loci
Authors: Gautam Pandey, Kevin Currin, Swarooparani Vadlamudi, Shelley Moxley, Jayna Nicholas, Jessica McAfee, Alaine Broadaway, Karen Mohlke
Journal: Circulation (2022)

Genome-wide association studies (GWAS) have identified hundreds of risk loci for cardiometabolic and lipid-related traits. GWAS loci are enriched in tissue-specific transcriptional regulatory elements that affect target gene expression driving physiological changes. Most GWAS variants are located in non-coding regions, which makes identifying functional variants and target genes challenging. Previously, we identified GWAS signals colocalized with molecular quantitative trait loci for liver gene expression (eQTL) and liver accessible chromatin (caQTL) to predict regulatory variants for lipid and cardiometabolic traits. These caQTLs are rs13395911, rs11644920, rs34003091 and rs9556404 associated with liver enzymes, LDL-cholesterol, and triglycerides. To evaluate the predicted mechanisms, we tested these variants with surrounding regulatory elements for allelic effects on transcriptional reporter activity and for effects on target gene expression in HepG2 cell line. Along with the two previously reported intronic caQTL variants, rs13395911 and rs11644920 , we observed significant (P&lt;0.05) allelic differences in transcriptional activity for rs9556404 and rs34003091, located at the promoters of GPR180 and ZNF329 , respectively. Based on eQTL and HiC data, the predicted genes for intronic enhancers rs13395911 and rs11644920 are EFHD1 and LITAF , respectively. To confirm the target genes for these two variants, we deployed inducible CRISPRi system by stably expressing dCas9 fused to a KRAB-repressor domain in HepG2 and targeting guide RNAs (gRNAs) to the DNA elements that span caQTL variants. For each element, we introduced ≥6 gRNAs into cells via lentiviruses and measured gene expression using qPCR. Compared to pools of non-targeted control gRNAs, preliminary analyses using pools of enhancer-targeting gRNAs surrounding rs13395911 and rs11644920 led to 30.3% lower EFHD1 and 38.6% lower LITAF expression at 7 days post-transduction, respectively. Thus, we identified and validated mechanisms by which DNA variants alter transcriptional activity and identified the target genes for lipid-related GWAS loci. These results suggest that this framework can be scaled up to map thousands of enhancers to genes in their native genomic state.
Abstract 233: Chest Compression Release Velocity In Pediatric In Hospital Cardiac Arrest: A Descriptive Study
Authors: Jennifer E Hayes, Tommy Rappold, Jordan Duval-Arnould, Dana Niles, Robert M Sutton, Annemarie E Silver, Marc Berg, Kasper G Lauridsen, Vinay M Nadkarni
Journal: Circulation (2022)

Introduction: Chest compression release velocity (CCRV) during chest compression (CC) recoil is understudied in pediatrics. Our objective was to characterize CCRV during pediatric in hospital cardiac arrest (IHCA). Methods: Using the PediRES-Q multicenter prospective observational cohort from 2015 to 2021, we analyzed patients &lt;18 years who received ≥ 20 minutes of CPR with quantitative CPR metrics (ZOLL R Series) across 30 sites. Median and Interquartile Range (IQR) CCRV, measured by pad integrated accelerometers, was defined as maximum velocity during CC recoil. CCRV was calculated for each CC and compared between 3 age groups. Initial (min 0-3), early (min 5-8), and late (min 15-20) periods of CPR were compared when metrics were available for all stages. Wilcoxon rank sum was used for comparisons. Results: Of 308 events with CC metric data and ≥ 20 min duration there were 106 (34%) &lt;1 yo, 114 (37%) 1&lt;8 yo, and 88 (29%) 8&lt;18 yo. Median [IQR] duration was 43 [31, 58] min. Median CCRV for &lt;1 yo: 152 [125, 179] mm/s; 1&lt;8 yo: 213 [177, 261] mm/s; and 8&lt;18 yo: 397 [294, 388] mm/s. Difference in CCRV between age groups was significant (p&lt;0.0001) with CCRV increasing as age increased. 185 events had complete CC metric data during initial (min 0-3), early (min 5-8), and late (min 15-20) periods of CPR. There was no significant difference in CCRV over time: initial 222 [159, 329] mm/sec; early 218 [154, 322] mm/sec; late 219 [163, 321] mm/sec. Similar lack of difference over time was demonstrated between the 3 age groups: &lt;1 yo initial 151 [113, 191] mm/sec; early 149 [119, 191] mm/sec; late 160 [127, 213] mm/sec; 1&lt;8 yo initial 222 [177, 277] mm/sec; early 237 [186, 276] mm/sec; late: 220 [185, 256] mm/sec; and 8&lt;18 yo initial 376 [270, 524] mm/sec; early 395 [277, 441] mm/sec; late 381 [280, 468] mm/sec. Conclusions: We characterized CCRV during pediatric IHCA as a metric of CPR performance related to chest recoil. CCRV was significantly slower for &lt;1 yo, faster for 1 to &lt;8 yo, and fastest for 8 to &lt;18 yo. Surprisingly, CCRV was not different over time (initial, early, late CPR periods). These findings suggest differences in CCRV related to patient age but do not demonstrate changes in CCRV over time in the first 20 minutes of CPR.
Abstract 14683: Cardiovascular Risk Perception in Young Patients With Coronary Artery Disease
Authors: Anish Adhikari, Georgeta Vaidean, Caleb Wutawunashe, Angela Yang, Chloe Findling, Roland Hentz, Eugenia Gianos
Journal: Circulation (2022)

Introduction: Risk perception is one of the factors influencing adoption of health protective behaviors, cardiac rehabilitation, and quality of life. While younger CAD patients tend to experience lower quality of life, their risk perception profile is less well-characterized. Methods: The Young Heart Study enrolled 60 patients ≤59 years old, with coronary artery disease noted on cardiac catheterization or CT coronary angiogram and at least two uncontrolled risk factors: BMI&gt;25 kg/m2, A1C &gt;7% in patients with diabetes, and &gt;5.6% in those without, systolic blood pressure &gt;130 mmHg, LDL&gt;70 mg/dL or active smoking. Perception of cardiovascular (CV) risk and health was collected via structured questionnaires. Results: Among the 60 patients in the study, the median age (Q1-Q3) was 51 (45-55), 70% were male, 46.7% were white. Participants had hypertension (76.7%), hyperlipidemia (91.7%), diabetes (36.7%), prediabetes (28.3%), obstructive CAD (88.3%), myocardial infarction history (38.3%), family history of premature ASCVD (48.3%) and self-reported depression or anxiety (11.7%). Health perception related questions were answered by 46 of these patients. Gender-specific waist circumference goals were not met in 54.6% and metabolic syndrome was noted in 60%. Most (91.7%) had a BMI greater than 25. Participants rated their CV risk as below average (21.7%), average (30.4%), and above average (47.8%) risk of peers of same age and sex. Only 8.3% identified a need for change to their medication regimen, despite most having biomarkers above targets (52.5% for LDL, 53.3% for BP, and 68.1% for A1c). Diet and physical activities were identified as areas for improvement by 83.3%, and weight by 72.9% of patients. Among smokers, all felt their smoking status could be improved. Most (68.1%) reported they were confident they could control their CV risk, while 21.3% answered neutral and 10.7% disagreed. Conclusion: In this above-average/high-risk population, we detected a gap between the clinician’s and patient’s CV risk perception. Exploring patient health perception in the clinic may identify areas for education and counseling. Future studies are needed to assess the impact of various interventions on perceived CV risk and on the adoption of cardio-protective behaviors.
Abstract 15112: Subcutaneous versus Transvenous Implantable Defibrillator Recipients: A Systematic Review and Meta-Analysis
Authors: Maryam Saleem, verda arshad, Pooneh Nabavizadeh, Faysal Alhasan, Duc H Do, Muhammad Rizwan Afzal, Raul Weiss, Alexandru Costea
Journal: Circulation (2022)

Introduction: Subcutaneous implantable cardioverter-defibrillator (S-ICD) is an alternative to transvenous implantable cardioverter-defibrillator (T-ICD) in select patients with complex anatomy, high infection risk and venous access issues. T-ICD is known to cause perioperative and long-term complications. Considering expanding indications for S-ICD, ongoing uncertainty in efficacy and unknown utility in low-risk patients, we performed this updated meta-analysis to study device related complications in both the systems. Methods: We performed a meta-analysis using electronic literature search to retrieve studies that compared S-ICD to T-ICD. Outcomes of interest were efficacy and device-related complications. Outcomes were pooled under random-effects and reported as risk ratios (RRs) and 95% CIs. 15 studies (observational, case-control and RCTs), median follow up 31.1 months, with variable heterogeneity for different outcomes (Fig-1), were included to capture real-world data. Results: A total of 21628 patients (S-ICD group n=3594, male 72.6%, mean age 50.1±10y and T-ICD group n=18034, male =72.6%, mean age 53.3±10.6y) were recruited. Lead-related complications were significantly lower in S-ICD, RR {0.21 [0.13, 0.34], P=&lt;0.00001}. There were no significant difference in other device-related endpoints: 30-day complications RR{0.67 [0.38, 1.18], P=0.17}; surgical complications RR{0.70 [0.49, 1.01], P=&lt;0.05}, inappropriate therapy RR{ 0.85 [0.67, 1.07], P=0.16}; appropriate therapy RR{ 0.62 [0.35, 1.09], P=0.10}, infections requiring surgery RR {0.84 [0.44, 1.59], P=0.59} and all-cause mortality RR{0.91 [0.68, 1.2, P=0.52]. Conclusion: Efficacy and safety of S-ICD is non-inferior to T-ICD and superior for lead-related complications.
Abstract 15768: Relative Longitudinal Strain Apical Sparing Pattern as a Detrimental Factor of Cardiovascular Outcome After Transcatheter Aortic Valve Replacement
Authors: Dan Liu, kai hu, Kolja Lau, Jonas Müntze, Octavian Maniuc, Peter Nordbeck
Journal: Circulation (2022)

Introduction: Several risk scores have been developed for outcome after heart surgery. However, risk factors associated with clinical outcome in patients undergoing transcatheter aortic valve replacement (TAVR) are still not well defined. This study aimed to determine laboratory and echocardiography determinants of short- and long-term outcome after TAVR. Methods: This retrospective study comprised 598 consecutive patients with sole aortic stenoseis (AS) who received balloon-expandable TAVR in our hospital (mean age 81.7±5.7 years, 48.7% male, median EuroSCORE II 5.0%). Pre-operative laboratory and imaging data including speckle-tracking echocardiography were analyzed. Clinical outcomes included cardiovascular (CV) death, CV hospitalization, and procedure related complications at 30 days, 1 year, and at 2 years after TAVR. Results: Semi-quantitative assessment defined as ≥3 LV wall segments with the apico-basal LS ratio &gt;3.0 was used to define relative apical sparing pattern (RASP). The prevalence of RASP was 19.2%. RASP patients had higher prevalence of acute kidney injury (AKI, 10.4% vs. 3.3%, P=0.001) and new-onset left bundle branch block (LBBB) after TAVR (17.4% vs. 6.8%, P&lt;0.001). CV mortality at 30 days (7.0% vs. 3.1%, P=0.062), 1 year (15.7% vs. 7.9%, P=0.010), and 2 years (22.6% vs. 9.9%, P&lt;0.001) was also higher after TAVR. RASP remained the strongest determinant for AKI (OR=3.11, P=0.007), new-onset LBBB (OR=2.89, P&lt;0.001), increased 30-day CV related hospitalization or death risk (OR=2.20, P=0.033). Lower albumin level and RASP were identified as independent determinants of increased 1-year and 2-year CV mortality risk (RASP: HR=1.83 and 2.18, P=0.039 and 0.002; albumin&lt;4.0g/dl: HR=3.18 and 2.55, both P&lt;0.001), regardless of TAVR approach and EuroSCORE II. After adjustment, the addition of RASP significantly improved prognostic power of a model including clinical variables and low albumin level for predicting CV death at 2-year follow-up ( χ 2 from 28.18 to 40.70, P=0.001). Conclusions: RASP represents a novel clinically relevant determinant of outcome after TAVR. Low albumin and RASP were identified as the strongest laboratory and echocardiography determinants for increased short- and long-term outcome after TAVR.
Abstract 15157: Prevalence and Burden of Concomitant Aortic Stenosis in Acute Myocardial Infarction Hospitalizations in the United States
Authors: Sri H Patlolla, Muhammad Haisum Maqsood, Saraschandra Vallabhajosyula
Journal: Circulation (2022)

Introduction: There are limited data on the prevalence, management and outcomes associated with concomitant aortic stenosis (AS) and acute myocardial infarction (AMI). Methods: All adult hospitalizations with a primary diagnosis of AMI were identified from the HCUP-NIS database (2000-2017). Admissions with a concomitant diagnosis of AS were compared to AMI admissions without AS. Outcomes of interest included prevalence of AS, in-hospital mortality, use of in-hospital cardiac procedures, hospitalization costs, length of stay, and discharge disposition. Results: During the study period, there were a total of 11,622,528 AMI admissions. Among these 513,688 (4.4%) were identified with concomitant AS. Adjusted temporal trends revealed an increase in prevalence of AS among STEMI (adjusted odds ratio [AOR] in 2017 vs 2000 1.15) and NSTEMI (AOR 2017 vs 2000 1.28) hospitalizations. AMI admissions with concomitant AS were on average older (78.8 ± 10.9 vs 67.1 ± 14.1), of female sex, had higher comorbidity, higher rates of NSTEMI (78.9% vs 62.1%), acute non-cardiac organ failure (13.4% vs 9.2%), and cardiogenic shock (5.1% vs 4.8%)(all p&lt;0.001) when compared to those without AS. Concomitant AS was associated with significantly lower use of coronary angiography (45.5% vs 64.4%), percutaneous coronary intervention (20.1% vs 42.5%), coronary atherectomy (1.7% vs. 2.8%), and mechanical circulatory support (3.5% vs 4.8%) (all p &lt;0.001), but had had higher rates of coronary artery bypass surgery and surgical aortic valve replacement (5.9% vs 0.1%) compared to those without AS. Admissions with AMI and AS had higher in-hospital mortality (9.2% vs. 6.0%; adjusted OR 1.12 [95% CI 1.10-1.13]; p &lt;0.001). Concomitant AS was associated with longer hospital stay (median [interquartile range] 5[3-8] vs 3[2-6]), more frequent palliative care consultations (6.5% vs 2.3%), and less frequent discharges to home (44.6% vs 63.3%) when compared to AMI admissions without AS. Conclusions: In this large nationwide study, an increase in prevalence of AS in both STEMI and NSTEMI hospitalizations was noted. AMI admissions with concomitant AS had lower use of guideline-directed therapies, higher in-hospital mortality, and longer hospital stays.
Abstract 15136: Matrix Mechanics Regulate Engineered Myocardial Microtissue Organization and Contractility
Authors: Samuel J DePalma, Austin E Stis, Darcy Huang, Javiera J Jilberto, Jason Lo, Christopher D Davidson, Aamilah Chowdhury, Maggie E Jewett, Adam S Helms, David A Nodsletten, Brendon M Baker
Journal: Circulation (2022)

Introduction: The mechanical function of the myocardium is dictated by cardiomyocytes (CMs) and the surrounding fibrous extracellular matrix (ECM). Due to limitations in existing approaches for engineering myocardial tissue, how CMs sense and respond to mechanical microenvironmental changes remains understudied. Here, we established a method for creating arrays of cardiac microtissues with highly tunable mechanical features by integrating synthetic, fibrous matrices and iPSC-CMs. Through real-time contractility readouts enabled, we explored how biomechanical cues influence engineered cardiac tissue assembly and function. Methods: Arrayed cardiac microtissues were generated by selectively photo-crosslinking electrospun dextran vinyl sulfone fiber matrices onto pairs of microfabricated PDMS cantilevers. Subsequently, iPSC-CMs were patterned onto matrices using a microfabricated seeding mask. Matrix and cantilever stiffnesses were tuned by adjusting photoinitiator concentrations and cantilever geometry, respectively. Results: In tissues contracting against soft cantilevers (0.41 N/m), tissue contractile stress decreased with increasing matrix stiffness (E = 0.68 to 17.3 kPa). We also observed an increase in contractile stress on soft and aligned matrices, compared to non-aligned matrices. However, tissues contracting against stiffer cantilevers (1.2 N/m) exerted similar contractile stresses independent of matrix alignment. This may be explained by the enhanced alignment of myofibrils in non-aligned matrices contracting against stiffer posts. The size of vinculin-rich cell-ECM adhesion decreased on stiff matrices. Vinculin also localized to z-discs forming organized costameres on soft matrices. Tissue response to mavacamten suggests that β-cardiac myosins are required for costamere formation and myofibril maturation. Conclusions: We developed a new microfabrication strategy to create tunable cardiac microtissues and examined how biomechanical cues affect tissue assembly and function. We found that matrix stiffness, matrix alignment, and tissue constraint distinctly affect iPSC-CM function and structure, potentially due to differential influences on costamere formation and myofibrillar assembly.